Circumferential aerosol device

ABSTRACT

The present application discloses devices and methods for delivering a therapeutic compound to the olfactory epithelium of an animal or human. The device having one or more channels for imparting a circumferential and axial velocity to the discharged fluid, and an outlet that discharges an aerosol spray having a circumferential and axial velocity as it enters the nasal cavity of a user. The device is designed to displace the air in the upper nasal cavity in order to specifically deposit a therapeutic agent on the olfactory epithelium while minimizing pressure and discomfort experienced by the user.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.12/866,448, filed Oct. 22, 2010, now U.S. Pat. No. 8,757,146, which isthe national stage of International Application No. PCT/US2009/033468,filed Feb. 6, 2009, which claims the benefit of U.S. Provisional PatentApplication No. 61/027,002, filed Feb. 7, 2008; each application isincorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENT LICENSE RIGHTS

This invention was made with U.S. Government support under Grant Nos.AI052663 and 5R01A177390-04 awarded by the National Institutes of Health(NIH). The U.S. Government has certain rights in the invention.

BACKGROUND

Depositing therapeutic drugs on the olfactory epithelium has been shownto lead to rapid and direct uptake into the brain. This directnose-to-brain delivery route bypasses the blood-brain-barrier, whichkeeps a majority of drugs or drug candidates from reaching the brain inany significant concentrations. Many studies, including those of thepresent inventors, have shown that depositing a drug on the olfactoryepithelium, while minimizing drug absorption on the respiratoryepithelium, is key to maximizing the fraction of drug that bypasses theblood-brain-barrier and reaches the brain.

Currently there are no suitable nasal delivery devices that sufficientlytarget the olfactory region of the nasal cavity while avoiding the lungsand respiratory area of the nasal cavity. The olfactory region is anarrow space at the top of the nasal cavity taking up about 10% of thetotal surface area of the nasal cavity. In addition, when a subjectbreaths in through the nose, the inhaled air travels primarily along thelower part of the nasal cavity into the trachea and lung, thus, leavingthe air in the olfactory region mainly undisturbed and stagnant in theolfactory region (and hence leading to a low fraction of olfactory drugexposure for drugs carried along the breath path).

The present disclosure overcomes the disadvantages associated with theanatomical impediments described above by providing pressurizedolfactory drug delivery devices and methods for deliveringpharmaceutical compounds to the olfactory epithelium.

SUMMARY

The present application discloses a pressurized olfactory drug deliverydevice for producing an aerosol nasal spray having a narrow spray plumewith circumferential velocity. The device disclosed herein is designedto displace the residual olfactory air volume to deliver therapeuticcompound to the olfactory region of the nasal cavity. In one aspect, thepressurized olfactory drug delivery device comprises a container havinga mixture of a pressurized fluid and a therapeutic compound, a deliverydevice defining a longitudinal axis connected to the container andhaving an exit opening at the nasal-proximal end, a cylindrical channelconnected to the outlet of the container and extending to the exitopening, and a plurality of discharge outlets radially disposed aroundthe longitudinal axis, wherein each discharge outlet is oriented todischarge the pressurized fluid mixture in an axial and circumferentialdirection. The device further comprises a metering device forselectively discharging the pressurized fluid through the outlets, suchthat the outlets produce a plurality of aerosol spray dischargescomprising the therapeutic compound that converge into a single sprayplume having a circumferential helical velocity.

In a second aspect, the pressurized olfactory drug delivery deviceincludes a container containing a mixture of a pressurized fluid and atherapeutic compound; a delivery device in communication with thecontainer, the delivery device having a plurality of longitudinalhelical channels, each helical channel comprising an inlet and an outletdisposed at the nasal proximal-most end of the device; and a meteringdevice for selectively discharging the pressurized fluid mixture throughthe helical channels. The outlets are configured to discharge aplurality of aerosol spray jets comprising the pressurized fluid mixturethat converge into a single spray plume having a circumferential helicalvelocity as the spray exits the device.

The present application also discloses a method for depositing atherapeutic compound on the olfactory epithelium in the nasal cavity ofa human or animal subject, the method comprising administering apressurized fluid comprising the therapeutic compound from a pressurizedolfactory drug delivery device into the nasal cavity, wherein the devicedischarges a pressurized aerosol spray comprising the therapeuticcompound, the pressurized aerosol spray having a circumferentialvelocity after exiting the device.

This summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This summary is not intended to identify key features ofthe claimed subject matter, nor is it intended to be used as an aid indetermining the scope of the claimed subject matter.

DESCRIPTION OF THE DRAWINGS

The foregoing aspects and many of the attendant advantages of thisinvention will become more readily appreciated as the same become betterunderstood by reference to the following detailed description, whentaken in conjunction with the accompanying drawings, wherein:

FIG. 1 is a schematic illustration of a pressurized olfactory drugdelivery device constructed in accordance with one embodiment of thepresent disclosure;

FIG. 2A is a partial cross sectional view of the nasal delivery deviceof FIG. 1;

FIG. 2B is a partial cross sectional view of the nasal delivery deviceof FIG. 1 in operation;

FIG. 3 is a partial cross sectional view of a pressurized olfactory drugdelivery device according to a second embodiment of the presentdisclosure;

FIG. 4 is a cross sectional view of a pressurized olfactory drugdelivery device according to a third embodiment of the presentdisclosure;

FIG. 5 is a partial cross sectional view of a pressurized olfactory drugdelivery device according to a fourth embodiment of the presentdisclosure;

FIG. 6A is an axial view of the nozzle of FIG. 5;

FIG. 6B is an isometric view of the upper portion of the nozzle of FIG.5;

FIG. 6C is an isometric view of the lower portion of the nozzle of FIG.5;

FIG. 7 is a partial cross sectional view of a pressurized olfactory drugdelivery device according to a fifth embodiment of the presentdisclosure;

FIG. 8A is a cut-away view of a pressurized olfactory drug deliverydevice according to a sixth embodiment of the present disclosure;

FIG. 8B is a top perspective view of the embodiment of the device shownin FIG. 8A.

FIG. 8C is an exploded view of the embodiment of the device shown inFIG. 8B.

FIG. 8D is a bottom perspective view of the embodiment of the deviceshown in FIG. 8A.

FIG. 8E is an exploded view of the embodiment of the device shown inFIG. 8D.

FIG. 9 is a graph illustrating the particle size produced by a device ofthe present disclosure, as described in Example 1;

FIG. 10 is a graph illustrating the penetration of blue dye into thenasal cavity of rats administered using a device according to oneembodiment of the present disclosure, wherein the dye was administeredfrom the device at different air pressures, and each horizontal barrepresents the mean value for 4-6 rats and the error bars representstandard deviation, as described in Example 1;

FIG. 11 is a series of photographs illustrating the spray patternproduced by a device of the present disclosure on the left hand side,and a device that does not impart a circumferential velocity to thespray pattern on the right hand side, as described in Example 1;

FIG. 12A shows the simplex air flow pattern and velocity of the sprayfrom a flow simulation using an outlet without circumferential velocityin a flow simulation, demonstrating poor penetration of the cone, asdescribed in Example 2;

FIG. 12B shows the circumferential flow pattern and velocity of thespray from a flow simulation using a nozzle with a single outlet withcircumferential movement, demonstrating poor penetration of the cone, asdescribed in Example 2;

FIG. 12C shows the rotational flow pattern and velocity of the sprayfrom a flow simulation using an embodiment of a device of the presentdisclosure illustrated in FIG. 6, demonstrating improved penetration ofthe cone due to a narrow spray with circumferential and axial velocity,as described in Example 2; and

FIG. 12D illustrates the flowstreams from the spray pattern shown inFIG. 12C.

DETAILED DESCRIPTION

The present application discloses a pressurized olfactory drug delivery(PODD) device that produces an aerosol nasal spray having a narrow sprayplume with circumferential velocity. The device disclosed herein isdesigned to displace the residual olfactory air volume under lowpressure to increase the efficiency and consistency with whichpharmaceutical compounds are delivered to olfactory epithelium, andfurther to enhance patient tolerability.

A pressurized olfactory drug delivery device (PODD) 10 according to oneembodiment of the present disclosure is best seen by referring toFIG. 1. The device 10 comprises a pressurized tank 20 suitable forstoring a pressurized fluid, such as a compressed gas or propellant. Thecompressed gas may be compressed air, nitrogen, or any other suitablenon-toxic gas. The propellant may be a pressurized fluid such aschlorofluorocarbon (CFC) or hydrofluoroalkane (HFA). The pressurizedtank 20 is fluidically connected by tubing 22 to a pneumatic solenoid30. The pneumatic solenoid 30 is fluidically connected by tubing 32 toan air chamber 42. The air chamber 42 is connected via an internalcompartment to a nasal delivery device 40 having an applicator 50 withan orifice suitable for discharging an aerosol spray 60 into the nasalcavity of an animal subject. As used herein, the term aerosol refers toa suspension of fine solid or liquid particles in a gas, such as a mist.

Referring to FIG. 2A, the nasal delivery device 40 will now be describedin detail. In one embodiment, the nasal delivery device 40 comprises agenerally elongated tubular housing 142 having an exterior and interiorand a first opening or orifice 144 at one end (the nasal proximal end)that is radially aligned about the longitudinal axis of the housing, thehousing 142 being closed at the other end (the nasal distal end). Thehousing is preferably cylindrical in shape; however, any tubular shapemay be used. The housing further comprises a conically shaped applicator50 at the proximal end adjacent to and surrounding the orifice 144. Thehousing 142 surrounds a generally tubular, cylindrically shaped fluidreservoir 150 that extends along a portion of the longitudinal axis ofthe housing. The fluid reservoir has a proximal second orifice 154disposed near the first orifice 144 of the housing, the second orifice154 having a diameter smaller than that of the first orifice 144 andbeing generally radially aligned about the longitudinal axis of thehousing 142. The proximal end is conically shaped adjacent to andsurrounding the second orifice 154. The proximal portion 151 of thefluid reservoir 150 has a diameter narrower than the diameter of thehousing 142, thereby forming a channel 153 extending from the distalportion of the reservoir 152 to the orifice 154. The distal portion 152of the fluid reservoir 150 has a wider diameter, such that the exteriorsurface 158 of the fluid reservoir contacts the interior surface 146 ofthe housing 142, creating a seal that prevents flow of pressurized gasin a distal direction. The fluid reservoir 150 further comprises anelongated needle 156 whose long axis runs along the longitudinal axis ofthe housing 142 and is moveably disposed within the interior proximalportion of the fluid reservoir 150. The proximal end or tip 157 of theneedle 156 is configured to seal the second orifice 154 of the fluidreservoir. The fluid reservoir 150 preferably is provided with a vent(not shown) to prevent a vacuum that would increase the pressurerequired to remove fluid from the second orifice 154.

The housing 142 further comprises a spin chamber 160 defined by thespace between the interior surface 146 of the housing and the exteriorsurface 158 of the fluid reservoir. The housing further comprises acompressed gas inlet 148 that is in communication with the spin chamber160 and fluidically connected to the pneumatic solenoid 30. The spinchamber further comprises a coiled wire 162 that is wrapped around theexterior 158 of the fluid chamber, the coiled wire 162 having a helicalor corkscrew shape and extending from the gas inlet 148 to the proximalorifice 154.

Referring now to FIGS. 1 and 2B, the manner in which the embodiment ofthe PODD device 10 described above is used to deliver a pharmaceuticalcompound to the olfactory epithelium will now be described. When a userdetermines to discharge the pressurized nasal spray, the pneumaticsolenoid 30 is activated by a programmable timer to release thepressurized gas from tank 20 for a predetermined amount of time. Thepressurized gas released from the tank 20 travels through tubing 22, 32to the air chamber 42 and through the air chamber 42 into the gas inlet148 of the housing 142, thereby entering the spin chamber 160 of thenasal delivery device 40. The pressurized gas that enters the spinchamber 160 encounters the coiled wire 162, causing the pressurized gas166 to flow around the exterior surface 158 of the fluid reservoir in ahelical or corkscrew-shaped path, such that the gas acquires acircumferential helical velocity or vortex-like velocity havingcircumferential vector and axial vector components. The termcircumferential velocity also includes tangential velocity, helicalvelocity, vortical velocity, and similar terms.

Referring now to FIG. 2B, when the solenoid 30 is activated, theelongated needle 156 disposed within the fluid reservoir 150 isretracted from the orifice 154, thereby providing a narrow opening 168for the fluid within the fluid reservoir 150 to escape. As thepressurized gas 166 leaves the orifice 144, it creates a partial vacuumwhich forces fluid out of the reservoir 150 through the orifice 154. Thefluid is aerosolized due to the narrowness of the gap 168. Theaerosolized spray 170 is discharged from the nasal spray device 40 as aspray plume having a circumferential velocity and axial velocity as thespray plume enters the nasal cavity. The circumferential velocity hasthe advantage that the aerosol spray penetrates the upper nasal cavityallowing direct deposition of aerosolized therapeutic compounds on theolfactory epithelium.

The nasal delivery device can be used to deposit numerous types oftherapeutic compounds and compositions on the olfactory epithelium,including neurological, analgesic, anti-viral and cancer treatmentcompounds. Compounds that can be delivered include, but are not limitedto, compounds comprising small molecular weight synthetic organicpharmaceuticals, peptide and protein therapeutic compounds, antibodiesand antibody fragments, aptamer compounds, and DNA and RNA compounds.The compounds can be delivered as part of a composition or formulationto aid in stability or penetration of the olfactory epithelium. Thecomposition may further comprise stabilizers, preservatives, oradditives mixed with the therapeutic compound.

Referring to FIG. 3, a first alternate embodiment of a pressurizedolfactory drug delivery device 200 will be hereinafter described. Thedevice 200 comprises a tubular housing 210 having a central longitudinalaxis, an exterior surface 212, an interior surface 214, and a firstorifice 216 at the proximal end 218 thereof. The proximal end 218 of thehousing 210 is preferably conically shaped to facilitate discharge of apressurized nasal spray into the nasal cavity.

The device 200 further comprises a cylindrical fluid reservoir 230 thatis radially disposed about the longitudinal axis and enclosed by thehousing 210. The fluid reservoir 230 has an exterior surface 232 and aninterior surface 234 and a second orifice 236 at the proximal enddisposed near the first orifice 216 of the housing, the second orifice236 having a diameter smaller than that of the first orifice 216 andbeing generally radially aligned about the longitudinal axis of thehousing 210. The fluid reservoir 230 has a diameter narrower than thediameter of the housing 210. The proximal end of the fluid reservoir 230is conically shaped adjacent to and surrounding the second orifice 236.The fluid reservoir 230 preferably is provided with a vent (not shown)to prevent a vacuum that would increase the pressure required to removefluid from the second orifice 236.

The distal end of the housing 210 comprises one or more nozzles 220 thatare fluidically connected to a compressed fluid container 222. Thecompressed fluid may be compressed air, compressed nitrogen, or acompressed propellant such as CFC or HFA, or any other suitablepropellant recognized in the art. The compressed fluid containerpreferably has a metering device (not shown) to deliver a predeterminedamount of fluid, gas or propellant when activated. In some embodiments,the compressed fluid container is a MDI. The proximal end of the nozzles220 have openings 224 that open into a spin chamber 240 defined by thespace between the exterior surface 232 of the fluid reservoir 230 andthe interior surface 214 of the housing 210. The nozzles 220 areconfigured such that the openings 224 discharge the compressed fluid ina circumferential and axial direction, thereby establishing acircumferential velocity to the pressurized fluid.

With continued reference to FIG. 3, the manner in which the embodimentof the PODD device 200 described above is used to deliver apharmaceutical compound to the olfactory epithelium will now bedescribed. A user actuates the pressurized gas container 222 to releasea predetermined amount of pressurized gas 250 into the spin chamber 240.The pressurized gas acquires a circumferential velocity having an axialand circumferential component and exits the first orifice 216. As thepressurized gas 250 leaves the first orifice 216, it creates a partialvacuum which forces fluid out of the reservoir 230 through the secondorifice 236. The fluid is aerosolized due to the narrowness of the gap242 defined by the interior surface 214 of the first orifice 216 and theexterior surface 232 of the fluid reservoir 230. The aerosolized sprayis discharged from the nasal spray device 200, having a circumferentialvelocity as the aerosol spray 260 enters the nasal cavity.

Referring now to FIG. 4, a second alternate embodiment of thepressurized drug delivery device 300 will be hereinafter described. Thedevice 300 comprises a generally tubular cylindrical housing 310 havinga central longitudinal axis, an outer wall 311 having an exteriorsurface 312 an interior surface 314, and a first orifice 316 at thenasal-proximal end 318. The proximal end 318 of the housing 310 ispreferably conically shaped to enhance user comfort and facilitatedischarge of a nasal spray into the nasal cavity.

The housing 310 further comprises an inner wall 320 defining an axiallyaligned inner cylinder 322 open at both ends and connected to theproximal end 318 of the housing 310 at the orifice 316 and having adistal open end 324 disposed near the interior surface 315 of the distalwall of the housing, thereby defining a sufficient gap for receiving afluid between the distal open end 324 and the interior surface 315 ofthe wall. The inner cylinder 322 has a diameter less than the diameterof the outer wall 311, thereby defining a space between the exteriorsurface 326 of the cylinder 322 and the interior surface 314 of theouter wall 311 of the housing 310 that serves as a fluid reservoir 330suitable for storing a liquid pharmaceutical composition.

Referring still to FIG. 4, the device 300 further comprises a secondinner cylinder 340 having an exterior surface 341 and interior surface343, wherein the longitudinal axis of the second inner cylinder 340 isaxially aligned with the longitudinal axis of the housing 310. Thesecond inner cylinder 340 extends from a second orifice 342 at the nasalproximal end to an opening 344 at the distal end of the housing 310 thatis fluidically connected to a pressurized fluid container 346. Thediameter of the second inner cylinder 340 is less than the diameter ofthe first inner cylinder 322, thereby defining a tubular channel 350that extends from the distal open end 324 of the first inner cylinder322 to the first orifice 316. A metering device 348 is fluidicallyconnected to the pressurized fluid container 346 at one end, and to theopening 344 in the distal end of the second inner cylinder 340 at theother end. The interior surface 343 of the cylinder 340 defines achannel 354 that functions as a spin chamber, the channel 354 beingconnected at one end to the metering device 348 and at the other end tothe second orifice 342. A plurality of discharge vents 530 are disposedbetween the metering device 348 and the interior of the channel 354, thedischarge vents 530 being in fluid connection with the metering device348. The plurality of discharge vents 530, which are better seen withreference to FIGS. 5 and 6, are configured to discharge a pressurizednasal spray having a circumferential axial velocity. In an alternativeembodiment, the pressurized fluid container 346 can be substituted witha metered dose inhaler (MDI).

With continued reference to FIG. 4, the manner in which the embodimentof the PODD device 300 described above is used to deliver apharmaceutical compound to the olfactory epithelium will now bedescribed. A user actuates the pressurized fluid container 346 andmetering device 348 to release a predetermined amount of pressurizedfluid 360 into the second inner cylinder 340. In the embodimentillustrated in FIG. 4, the pressurized fluid 360 is a pressurized gas.The pressurized gas 360 passes through the metering device 348 and theplurality of discharge vents 530 thereby acquiring a circumferentialaxial velocity, enters the spin chamber 354, and exits the secondorifice 342. As the pressurized fluid 360 leaves the second orifice 342,it creates a partial vacuum which forces fluid up the tubular channel350. The fluid is aerosolized due to the narrowness of the gap 352defined by the interior surface 328 of the first inner cylinder 322 andthe exterior surface 341 of the second inner cylinder 340. Theaerosolized spray is discharged from the first orifice 316 as a sprayplume 370 having a circumferential velocity as the aerosol spray 370enters the nasal cavity. The fluid reservoir 330 preferably is providedwith a vent (not shown) to prevent a vacuum that would increase thepressure required to remove fluid from the second orifice 342.

Referring now to FIG. 5, a fourth alternate embodiment of thepressurized drug delivery device 500 will be hereinafter described. Thedevice 500 comprises a cylindrical tubular housing 510 having alongitudinal axis with an outlet 516 located at the proximal end 518thereof, wherein the proximal end 518 of the housing 510 is preferablyconically shaped and functions as a nose cone to enhance user comfort.The housing 510 further comprises flanges 512 located near the distalend that aid in operation of the device by a user. The distal end 519 ofthe housing 510 is connected to the proximal end member 520 of apressurized fluid container 522 comprising a metering device 524. Themetering device 524 delivers a predetermined amount of fluid, gas orpropellant when activated. Alternatively, the pressurized fluidcontainer 522 is an MDI. The metering device may further deliver apredetermined dose of a therapeutic compound provided as a mixture withthe pressurized fluid. The device 500 further comprises a plurality ofaerosol discharge vents 530 configured to discharge a pressurized nasalspray having a circumferential velocity.

Referring now to FIGS. 6A-C, the aerosol discharge vents 530 will bedescribed in detail. Each vent 530 has an elongated rectangular or ovoidcross section, and a slit-like or slot-like proximal opening 532connected to a distal opening 534 by a channel. The vents 530 areoriented generally radially wherein the angle of the proximal-distalaxis of each vent 530 is oblique to the longitudinal axis of the device500 such that an aerosol discharged from the vent has a circumferentialand axial component. As shown in FIG. 6C, the distal opening 534 of eachvent is fluidically connected to the proximal end member 520 of thepressurized gas container 522. It will be understood that each vent maybe constructed such that the vent structure extends above the surfacecreated by the proximal end 520 of the pressurized gas container 522,or, in the alternative, the vents may consist of openings in theproximal end 520 of the pressurized gas container 522, or any othersuitable configuration.

Referring now to FIGS. 5 and 6A-C, the manner in which the embodiment ofthe PODD device 500 described above is used to deliver a pharmaceuticalcompound to the olfactory epithelium will now be described. A useractuates the pressurized gas container 522 to release a predeterminedamount of pressurized gas through the metering device 524 into thedistal opening 534 of each vent 530. The pressurized gas exits theproximal opening 532 of each vent as an aerosol 550 having an axialvelocity and a radial velocity (only one discharged aerosol 550 is shownfor simplicity). The discharged aerosols 550 exiting each vent convergeinto a single pressurized nasal spray pattern 560 having acircumferential velocity that then exits the device through the outlet516. The proximal end 518 of the housing 510 serves as a nose cone toaid the user in aligning the device with the nostril to deliver thepressurized nasal spray having a circumferential velocity into the nasalcavity. However, it will be understood that the housing 510 is notrequired to produce the circumferential velocity of the spray, and thatthe housing illustrated in FIG. 5 is provided for the convenience of theuser. Further, as described in Example 2, flow simulation of the spraypattern produced by a plurality of vents or outlets similar to theembodiment described in FIG. 6 produces a narrow spray plume havingcircumferential and axial velocity. Therefore, a device having aplurality of outlets as described in a representative embodiment of thepresent disclosure, such as that illustrated in FIG. 6, does not requirea spin chamber or other type of chamber at the proximal end of thedevice for producing a spray plume having circumferential velocity.

The circumferential velocity created by the plurality of vents has theadded advantage that the spray plume is able to penetrate the upperregions of the nasal cavity compared to a spray plume produced withoutcircumferential velocity, and be much more narrow than the wide sprayplume produced by a device having a single aerosol source with vorticalflow, which further helps the spray to penetrate the upper nasal cavityand contact the olfactory epithelium.

Referring now to FIG. 7, a fifth alternate embodiment of the pressurizeddrug delivery device 600 will be hereinafter described. The embodimentillustrated in FIG. 7 shares many of the features described above forFIG. 5, including a housing 610 having an outlet 616 surrounded by aconical proximal end 618 that functions as a nose cone. However, insteadof a plurality of discharge vents 530, the device 600 comprises aplurality of discharge nozzles 630 fluidically connected to apressurized fluid container 622 comprising a metering device 624.Alternatively, the pressurized fluid container 622 can be substitutedwith an MDI. Each nozzle 630 is configured to discharge an aerosol sprayin an axial and circumferential direction such that each individualaerosol spray converges into a single pressurized spray pattern 660having a circumferential velocity. The housing 610 further comprisesflanges 612 located near the distal end that aid in operation of thedevice by a user. As described above, it is understood that the housing610 is not required to produce the circumferential velocity of thespray.

In the embodiments illustrated in FIGS. 5-7, the pressurized fluidcontainer preferably contains a mixture of compressed fluid and atherapeutic compound. The compressed fluid may be any non-toxicpropellant known in the art, for example compressed air, or apressurized propellant such as chloro fluorocarbon (CFC) orhydrofluoroalkane (HFA).

Referring now to FIG. 8A-E, a delivery device or nozzle 700 for use witha pressurized drug delivery device will be hereinafter described. Thenozzle 700 is cylindrically shaped defining a longitudinal axis, andhaving nasal-proximal end and nasal-distal ends, an inner cylinderportion 710, an outer cylinder portion 720, and a plurality of outletorifices 730. The plurality of outlets 730 are radially disposed aroundthe longitudinal axis of the nozzle. In one embodiment, the outlets 730are symmetrically radially disposed around the longitudinal axis of thenozzle. In one embodiment, the plurality of outlets 730 are disposed ona surface at the nasal-proximal end of the nozzle. In one embodiment, atleast three outlet orifices 730 are provided. In the embodimentillustrated in FIG. 8A-E, six outlet orifices 730 are provided.

Still referring to the embodiment illustrated in FIG. 8A-E, the innercylinder 710 has a conical extension 712 disposed at the nasal-proximalend to aid the user in directing a pressurized nasal spray into thenasal cavity. However, it is to be understood that the conical extension712 is optional and not required for the operation of the nozzle.Further, in some embodiments, the nasal-proximal end of the nozzle maybe protected by a nose cone (not shown) to enhance the comfort of theuser.

With continued reference to FIG. 8A-E, each outlet orifice 730 isconnected to an inlet orifice 740 by an axial channel 750 having acorkscrew, helical or spiral shape. Each channel is an enclosed volumeor space defined by the lateral surfaces 762 of corkscrew-shaped axialmembers 760 that extend along and rotate about the longitudinal axis ofthe nozzle, the exterior surface 714 of the inner cylinder portion 710,and the interior surface 722 of the outer cylinder portion 720.

The nozzle 700 may be constructed by machining threads or grooves in theexterior surface 714 of the inner cylinder portion 710 to produce thecorkscrew shaped axial members 760 thereof. Alternatively, the nozzle700 may be constructed by machining threads or grooves in the interiorsurface 722 of the outer cylinder portion 720 to produce the corkscrewshaped axial members 760 thereof. It is understood that the nozzle isnot limited by the method of producing or manufacturing the nozzle.

In a preferred embodiment, the cross-sectional area of the channeldecreases from distal to proximal, such that the outlets 730 are smallerthan the inlets 740, thereby providing acceleration to a pressurizedfluid entering the channel. It will be understood that the channels maybe round, square, rectangular, ovoid, or any other suitable shape incross section. The outlets 730 are configured such that a pressurizedfluid discharged from the outlet has an axial velocity and acircumferential velocity. The outlets 730 are further configured toatomize the pressurized fluid into an aerosol spray as the pressurizedfluid exits the outlets 730. Further, in some embodiments, the outlets730 are configured such that the aerosol spray discharged from theoutlet is further directed radially inwardly at an oblique angle towardthe longitudinal axis of the nozzle.

Referring again to FIGS. 8A-E, the manner in which the embodiment of thenozzle 700 described above is used to deliver a pharmaceutical compoundto the olfactory epithelium of a human or animal subject will now bedescribed. In one embodiment, the nozzle 700 will be attached to apressurized fluid container (not shown) containing a mixture ofpressurized fluid and a therapeutic compound or pharmaceuticalcomposition. In other embodiments, pressurized fluid container comprisesa metering device that provides a predetermined amount of pressurizedfluid comprising a predetermined dosage of a therapeutic compound whenactivated. In a preferred embodiment, the pressurized fluid container isa metered dose inhaler. The pressurized fluid may be a compressed gas,such as compressed air, or a propellant known in the art. In operation,pressurized fluid discharged from the pressurized fluid container entersthe plurality of inlets 740, travels through the axial channels 750 andexits the outlets 730. The pressurized fluid becomes atomized into anaerosol spray discharge as it exits the outlets 730. After exiting theoutlets 730, each individual aerosol spray discharge converges into asingle spray pattern having circumferential velocity. In a preferredembodiment, the nasal-proximal end of the nozzle is partially insertedinto the nasal cavity of the human or animal subject, and the singlespray plume maintains circumferential velocity as it exits the deviceand enters the nasal cavity. It is understood that the nozzle 700disclosed herein has the advantage that no spin chamber or other type ofchamber is required to induce the circumferential axial velocity of theaerosol spray plume; the circumferential flow is induced solely by theconfiguration of the axial channels 750 and the outlets 730.

The circumferential velocity created by the plurality of outlets 730 hasthe added advantages that the spray plume is able to penetrate the upperregions of the nasal cavity compared to a spray plume produced withoutcircumferential velocity, and is much narrower than the wide spray plumeproduced by a device having a single aerosol source with vortical flow.The narrow spray plume, in combination with the circumferential velocityprovided by the nozzle 700, allows the aerosolized spray to penetratethe upper nasal cavity and deposit therapeutic compounds on theolfactory epithelium. Representative methods for measuring the diameterof the spray plume are described in Example 1.

In some embodiments, the device of the disclosure discharges a pluralityof particles having an average or mean diameter in the range selectedfrom the group consisting of about 1 to about 100 micrometers, about 5to about 50 micrometers, about 5 to about 30 micrometers, about 5 toabout 25 micrometers, about 5 to about 20 micrometers, about 5 to about15 micrometers, and about 10 to about 15 micrometers. In someembodiments, at least 70%, at least 80%, at least 90% and at least 95%of the particles produced by the device have a diameter between about 5and 25 micrometers. In one embodiment, the majority of the particlesdischarged by the device are in the range of about 5 to 20 micrometers.Aerosol discharge outlet diameters for producing the desired particlesizes are typically in the range of 01. to 0.5 mm.

The disclosure further provides a method for depositing a therapeuticcompound on the olfactory epithelium in the nasal cavity of a human oranimal subject. In one embodiment, the method comprises administeringthe therapeutic compound from a pressurized nasal spray device into thenasal cavity, wherein the pressurized nasal spray device comprises anaerosol outlet that discharges a pressurized spray comprising thetherapeutic compound, the pressurized spray having a circumferentialvelocity as it exits the outlet and enters the nasal cavity.

In another embodiment the method comprises administering a pressurizedfluid comprising the therapeutic compound from a pressurized olfactorydrug delivery device into the nasal cavity, wherein the device comprisesa plurality of outlets that discharge a plurality of pressurized aerosolsprays comprising the therapeutic compound, the plurality of pressurizedaerosol sprays converging into a single spray plume having acircumferential velocity after exiting the device. In one embodiment,each outlet of the device is located at the nasal-proximal most end ofthe device and discharges the aerosol spray having a circumferentialvelocity directly into the nasal cavity.

In some embodiments, the method administers a plurality of particles tothe nasal cavity, the plurality of particles having an average or meandiameter in the range selected from the group consisting of about 1 toabout 100 micrometers, about 5 to about 50 micrometers, about 5 to about30 micrometers, about 5 to about 25 micrometers, about 5 to about 20micrometers, about 5 to about 15 micrometers, and about 10 to about 15micrometers. In other embodiments, at least 70%, at least 80%, at least90% and at least 95% of the particles administered by the method have adiameter between about 5 and 25 micrometers. In one embodiment, themajority of the particles administered by the method are in the range ofabout 5 to 20 micrometers.

In one embodiment, the device used in the method comprises a metereddose device that releases a predetermined amount of the pressurizedfluid comprising a predetermined dose of the therapeutic compound whenthe device is activated. In this embodiment, the method delivers about40% of the predetermined amount of the pressurized fluid that enters thenasal cavity as an aerosol spray to the olfactory epithelium. In otherembodiments, the method delivers at least about 40% of the predetermineddose of the therapeutic compound to the olfactory epithelium. In oneembodiment, the method results in higher concentrations of a therapeuticcompound in the brain than in the blood.

In some embodiments, the therapeutic compound of the method is providedas part of a composition or formulation containing stabilizers,preservatives, or additives that are well known in the art. Further, insome embodiments, the therapeutic compound may be formulated withcolloids, nanoparticles, liposomes, micelles, or another type ofsuspension.

While not wishing to be bound by theory, the devices and methodsdescribed in the above embodiments are believed to improve thepenetration of an aerosol spray into the upper nasal cavity bydisplacing the resident or residual air volume present in the uppernaval cavity. This allows a larger fraction of the therapeutic compoundto be deposited directly on the olfactory epithelium while at the sametime reducing the amount of the therapeutic compound that is depositedon the respiratory epithelium, esophagus, stomach and lungs. A furtheradvantage of the devices described in the present disclosure is areduction in the back pressure required to deliver drugs to theolfactory epithelium when compared to devices that deliver a narrowspray plume without a corresponding centrifugal velocity component.

EXAMPLE 1

This example describes various functional parameters of the deviceillustrated in FIGS. 1 and 2.

The spray rate was tested by varying the driving pressure from 1 to 6pounds per square inch and the diameter of the orifice 154. The sprayrates were reproducible and within the desired range for humanapplication, namely less than 50 microliters per second.

FIG. 9 shows the particle size distribution when water was sprayed fromthe device into viscous oil at a distance of 2 cm and 4 psi, and theresulting droplet diameters were measured using a microscope with sizeanalysis software. A total of 199 measurements were made. Thedistribution shows that the device produces particles having diametersof from 5 to greater than 50 microns, and that the majority of theparticle diameters are between 5 and 20 micrometers, with an averagediameter of 11.2 microns. The size distribution obtained by this methodof atomization is therefore desirable for nasal spray applications.

FIG. 10 shows the penetration of an aerosolized blue dye into the nasalcavity of rats using the device illustrated in FIGS. 1 and 2 compared tothe penetration of nose drops. Rats have a maximum naval cavity distanceof about 2.5 cm. Increasing the air pressure of the device increases thepenetration into the nasal cavity and coverage of the olfactoryepithelium. The nasal drops resulted in no deposition on the olfactoryepithelium, while the 3 psi spray from the PODD resulted inapproximately 15% deposition on the olfactory epithelium, and the 4 psispray from the PODD resulted in approximately 40% deposition on theolfactory epithelium. The results presented in FIG. 10 indicate thatbetween 3-5 psi, a maximum penetration in nasal cavity is achieved toproduce an optimal result. Higher pressures were untested but could leadto even deeper penetration into the nasal cavity.

FIG. 11 shows the spray pattern produced by the device using a blue dyemarker sprayed out of the device at various distances from a piece ofpaper. The left-hand side of FIG. 11 illustrates the circumferentialflow as the angle of the majority of the dye shifts radially as thedistance from the nozzle changes. The right-hand side of FIG. 11illustrates the symmetrical pattern produced by a spray nozzle that doesnot impart a circumferential velocity to the aerosol spray.

Table 1 shows the delivery of the antiviral drug nelfinavir to differentbrain regions in rats using nose drops (which approximates nasaldistribution with a standard nasal spray) or the PODD device illustratedin FIGS. 1 and 2. 30 minutes after delivery, the PODD device delivered42.7% of the drug dose present in the nasal spray to the olfactoryepithelium compared to 4.7% of the dose delivered by nose drops. Thedrug concentrations were higher in various brain regions and lower inthe blood when delivered using the PODD device.

TABLE 1 Distribution of nelfinavir in rats 30 minutes after delivery vianose drops or using a pressurized olfactory drug delivery device of thepresent disclosure. Nelfinavir concentration (nmol/g tissue) drops PODolfactory bulbs 0.137 ± 0.104 0.409 ± 0.057 cortex 0.011 ± 0.003 0.083 ±0.008 diencephalon 0.069 ± 0.027 0.205 ± 0.02  cerebellum 0.071 ± 0.0080.302 ± 0.073 brainstem 0.087 ± 0.026 0.117 ± 0.052 blood 0.0159 ±0.025  0.053 ± 0.010 olfactory delivery 4.7% 42.7%

The results presented in this Example show that the device and methodsdisclosed in the application are useful for delivering therapeuticcompounds to the olfactory epithelium and brain regions, and that alarge fraction of the dose present in nasal spray having acircumferential velocity is deposited on the olfactory epithelium. Theresults also show that the device delivers a high fraction of drug tothe olfactory epithelium, which leads to higher drug concentrations inthe brain and lower drug concentrations in the systemic circulation.

EXAMPLE 2

This example demonstrates the improved penetration of a simulated nosecone using a device comprising a plurality of outlets in comparison to adevice having a single outlet with and without circumferential flow.

Methods:

Flow simulations were carried out using the Star-CCM+ computationalfluid dynamics simulation software package (CD-adapco), version3.06.006. In the simulation, a cone was used with similar geometry to anasal cavity for the sake of simplicity. The cone was designed to benarrow towards the top with the only outlet for residual air located atthe bottom of the cone. Thus, the air in the top of the cone wasstagnant and had to be displaced in order for the nozzle flow topenetrate the top of the cone, much like the upper nasal cavity of ahuman. The dimensions of the cone were 7.5 cm from top to bottom, inorder to realistically simulate nasal delivery to the olfactoryepithelium of a human.

The following nozzle structures were tested:

(1) a nozzle without circumferential flow and a single outlet;

(2) a nozzle with circumferential flow and a single outlet; and

(3) a nozzle with circumferential flow and a plurality of outlets, inaccordance with an embodiment of a device of the present disclosure asillustrated in FIG. 6;

The various nozzle structures were place in the bottom of the cone withthe outlets pointed upward towards the top of the cone. The area of flowfor each of the nozzles was kept at 3.54 mm² and the air velocity comingfrom the outlets was kept constant at 60 m/s. The simulation wasperformed under a steady time condition with k-epsilon turbulence. Thesimulations were run between 115 to 370 iterations until the momentumresiduals remained constant between iterations.

Results:

The results of the flow simulations are shown in FIGS. 12A-12D.

FIG. 12A shows the simplex air flow pattern and velocity of the sprayfrom a flow simulation using nozzle structure (1) having an outletwithout circumferential velocity. As shown in FIG. 12A, the simplex flowdoes a poor job of penetrating the cone because it cannot move the airin the narrow top of the cone, so the plume gets pushed off to thesides.

FIG. 12B shows the circumferential flow pattern and velocity of thespray from a flow simulation using nozzle structure (2) having an singleoutlet with circumferential velocity. As shown in FIG. 12B, the sprayflow coming out of the nozzle structure (2) having a single outlet withcircumferential velocity does not penetrate into the cone either becausea flow with vortical flow coming out of one orifice tends to spread outwhen exiting the orifice.

FIG. 12C shows the circumferential flow pattern and velocity of thespray from a flow simulation using nozzle structure (3) having aplurality of outlets with circumferential velocity, in accordance withan embodiment of a device of the present disclosure as illustrated inFIG. 6. As shown in FIG. 12C, the spray flow has improved penetration ofthe cone and penetrates to the top of the cone due to its narrow sprayplume having circumferential and axial velocity, which allows fordisplacement of the air in the upper nasal cavity.

FIG. 12D illustrates the flowstreams from the spray pattern shown inFIG. 12C.

The flow simulation comparison using the various nozzle structuresdescribed in this example demonstrates the advantages of using a nozzlehaving a plurality of outlets which generates a narrow spray patternhaving circumferential velocity to penetrate a narrow area, such as theupper nasal cavity of a human, where the air must be displaced to allowfor penetration of the spray in order to deposit a large fraction ofdrug on the olfactory epithelium.

While illustrative embodiments have been illustrated and described, itwill be appreciated that various changes can be made therein withoutdeparting from the spirit and scope of the invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A pressurized olfactorydrug delivery device comprising: (a) a container comprising a mixture ofa pressurized fluid and a therapeutic compound, the container at adistal end of the pressurized olfactory drug delivery device; (b) anozzle delivery device defining a longitudinal axis and having: (i) aninner axial member having a cylindrical core, (ii) a plurality ofhelical channels, the helical channels having a radial dimension, abasal surface, and an apical surface, wherein the basal surface is incontact with an outer surface of the axial member, and (iii) an outercylindrical member in contact with the apical surface of the helicalchannels, and (c) a metering device configured for selectivelydischarging the mixture of a pressurized fluid and a therapeuticcompound through the helical channels; wherein each helical channelcomprises an inlet for receiving the mixture of a pressurized fluid anda therapeutic compound, and an outlet for discharging the mixture of apressurized fluid and a therapeutic compound, the outlets being locatedat a proximal-most end of the pressurized olfactory drug deliverydevice, each outlet is configured to produce an aerosol spray having anaxial velocity and circumferential velocity, such that the axialvelocity and the circumferential velocity produced by each outletconverge into a single spray plume having a circumferential velocity. 2.The pressurized olfactory drug delivery device of claim 1, furthercomprising a conical extension, the conical extension located at theproximal-most end of the pressurized olfactory drug delivery device andcongruent with the inner axial member.
 3. The pressurized olfactory drugdelivery device of claim 1, wherein the helical channels spiral aroundthe longitudinal axis.
 4. The pressurized olfactory drug delivery deviceof claim 1, wherein the therapeutic compound comprises at least one ofsmall molecules, peptides, proteins, antibodies, antibody fragments,aptamers, or nucleic acids.
 5. The pressurized olfactory drug deliverydevice of claim 1, wherein the device delivers liquid or lyophilizedtherapeutic compounds.
 6. The pressurized olfactory drug delivery deviceof claim 1, wherein the therapeutic compound is delivered as aformulation comprising stabilizers, preservatives, or additives.
 7. Thepressurized olfactory drug delivery device of claim 1, wherein thetherapeutic compound is delivered as a formulation comprising colloids,nanoparticles, liposomes, or micelles.